RESUMO
To an outsider, the exploration of thousands of molecules to find a small number of potential candidate drugs must appear enormously wasteful, but many medicinal chemists would defend this waste as unavoidable. Here, I provide evidence that suggests that modern medicinal chemists are overproductive in that they synthesise many more compounds than are required to achieve the objectives of the project. The difficulties encountered in finding the data for the analysis presented here prompted the design and implementation of a more rigorous approach to capture the essence of a medicinal chemistry program. The result, medicinal chemistry knowledge sharing (MeCKS), was designed to capture and communicate emerging issues and their solutions to the medicinal chemistry community.
Assuntos
Química Farmacêutica/métodos , Desenho de Fármacos , Conhecimento , Aprendizagem , Preparações Farmacêuticas/química , Química Farmacêutica/educação , Humanos , Preparações Farmacêuticas/síntese químicaRESUMO
By careful analysis of experimental X-ray ligand crystallographic protein data across several inhibitor series we have discovered a novel, potent and selective series of iNOS inhibitors exemplified by compound 8.
Assuntos
Inibidores Enzimáticos/química , Isoxazóis/química , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Piridinas/química , Animais , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Isoxazóis/síntese química , Isoxazóis/farmacologia , Camundongos , Microssomos Hepáticos/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estrutura Terciária de Proteína , Piridinas/farmacologia , RatosRESUMO
Nitric oxide synthase (NOS) enzymes synthesize nitric oxide, a signal for vasodilatation and neurotransmission at low concentrations and a defensive cytotoxin at higher concentrations. The high active site conservation among all three NOS isozymes hinders the design of selective NOS inhibitors to treat inflammation, arthritis, stroke, septic shock and cancer. Our crystal structures and mutagenesis results identified an isozyme-specific induced-fit binding mode linking a cascade of conformational changes to a new specificity pocket. Plasticity of an isozyme-specific triad of distant second- and third-shell residues modulates conformational changes of invariant first-shell residues to determine inhibitor selectivity. To design potent and selective NOS inhibitors, we developed the anchored plasticity approach: anchor an inhibitor core in a conserved binding pocket, then extend rigid bulky substituents toward remote specificity pockets, which become accessible upon conformational changes of flexible residues. This approach exemplifies general principles for the design of selective enzyme inhibitors that overcome strong active site conservation.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Óxido Nítrico Sintase/antagonistas & inibidores , Sequência de Aminoácidos , Aminopiridinas/química , Aminopiridinas/farmacologia , Animais , Bovinos , Cristalografia por Raios X , Modelos Animais de Doenças , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Expressão Gênica , Humanos , Isoenzimas/antagonistas & inibidores , Masculino , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Molecular , Mutação , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Quinazolinas/química , Quinazolinas/farmacologia , RatosRESUMO
An efficient one-pot, three-component synthesis of substituted 1,2,4-triazoles has been developed, utilizing a wide range of substituted primary amines and acyl hydrazides.
Assuntos
Técnicas de Química Combinatória , Triazóis/síntese química , Indicadores e Reagentes , Estrutura Molecular , EstereoisomerismoRESUMO
4-Methylaminopyridine (4-MAP) (5) is a potent but nonselective nitric oxide synthase (NOS) inhibitor. While simple N-methylation in this series results in poor activity, more elaborate N-substitution such as with 4-piperidine carbamate or amide results in potent and selective inducible NOS inhibition. Evidently, a flipping of the pyridine ring between these new inhibitors allows the piperidine to interact with different residues and confer excellent selectivity.
Assuntos
Aminopiridinas/síntese química , Óxido Nítrico Sintase/antagonistas & inibidores , Aminopiridinas/química , Animais , Cristalografia por Raios X , Camundongos , Modelos Moleculares , Óxido Nítrico Sintase/química , Óxido Nítrico Sintase Tipo IIRESUMO
This paper describes the development of a QSAR model for the rational control of functional duration of topical long-acting dual D(2)-receptor/beta(2)-adrenoceptor agonists for the treatment of chronic obstructive pulmonary disease. A QSAR model highlighted the importance of lipophilicity and ionization in controlling beta(2) duration. It was found that design rules logD(7.4) > 2, secondary amine pK(a) > 8.0, yielded ultra-long duration compounds. This model was used successfully to guide the design of long- and ultra-long-acting compounds. The QSAR model is discussed in terms of the exosite model, and the plasmalemma diffusion microkinetic hypothesis, for the control of beta(2) duration. Data presented strongly suggests that beta(2) duration is primarily controlled by the membrane affinity of these compounds.